EP1458347B1 - Mindestens ein alkanolamid enthaltende zusammensetzung zur inhibierung der migration der langerhanszellen und deren verwendung - Google Patents
Mindestens ein alkanolamid enthaltende zusammensetzung zur inhibierung der migration der langerhanszellen und deren verwendung Download PDFInfo
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- EP1458347B1 EP1458347B1 EP02799126.4A EP02799126A EP1458347B1 EP 1458347 B1 EP1458347 B1 EP 1458347B1 EP 02799126 A EP02799126 A EP 02799126A EP 1458347 B1 EP1458347 B1 EP 1458347B1
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- migration
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- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
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- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 description 1
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
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Images
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/16—Amides, e.g. hydroxamic acids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/06—Antipsoriatics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P5/00—Drugs for disorders of the endocrine system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/75—Anti-irritant
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- A—HUMAN NECESSITIES
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- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
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- A—HUMAN NECESSITIES
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/005—Preparations for sensitive skin
Definitions
- the present invention relates to the cosmetic and pharmaceutical treatment, especially dermatological skin. More particularly, the present invention relates to a composition containing at least one active compound chosen from alkanolamides as defined in the claims, optionally in combination with at least one other compound such as a metalloprotease inhibitor, a PKC inhibitor, an agent anti-inflammatory agent, a soothing agent, an immunosuppressant, an ion chelator, an oxazolidinone, a carbamic acid derivative or an oxazoline for use in the treatments defined in the claims.
- compositions for topical application comprising a sphingoid free base and a ceramic of different formula alkanolamides according to the present invention since they comprise two long chains.
- the subject of the invention is also such a composition for its use as a medicament advantageously for inhibiting the migration of cells such as dermal dendrocytes, monocytes, lymphocytes, and in particular Langerhans cells, for example following an external stimulus or " signal danger "chemical, physical, biological and more particularly immune, the intensity of which would be large enough to induce a disturbance of cutaneous homeostasis, for the treatments defined in the claims.
- cells such as dermal dendrocytes, monocytes, lymphocytes, and in particular Langerhans cells, for example following an external stimulus or " signal danger "chemical, physical, biological and more particularly immune, the intensity of which would be large enough to induce a disturbance of cutaneous homeostasis, for the treatments defined in the claims.
- Alkanolamides as defined in the claims, as well as their combination with a metalloprotease inhibitor, a PKC inhibitor, an anti-inflammatory agent, a soothing agent, an immunosuppressant, an ion chelator, an oxazolidinone, a carbamic acid derivative or an oxazoline and the pharmaceutical compositions comprising them are useful for the preparation of medicaments intended for the treatment or prevention of cutaneous pathologies of allergic and / or inflammatory origin.
- the subject of the invention is also a composition as defined in the claims for its use in a method of treating skins and / or mucous membranes that are sensitive, irritated, intolerant, with an allergic tendency, aged, subject to a danger signal, presenting a skin barrier disorder, presenting skin rash, or presenting a disorder, an imbalance or a non-pathological immunological disorder, of applying such a composition to the skin and / or the mucous membranes.
- One of the main functions of the skin is the protection of the body against attacks from the outside environment. This protection is provided in large part by the cooperation of cells present in the skin, cells that are capable in the presence of a harmful agent to generate an inflammatory and / or immune response directed against the harmful agent. These are dendritic cells, Langerhans (CL) cells of the epidermis, and dermal dendrocytes, monocytes, lymphocytes, keratinocytes, mast cells, and vascular endothelial cells.
- CLs are dendritic cells from the spinal cord that reside in non-lymphoid tissues such as the skin and mucous membranes (mouth, lung, bladder, rectum, vagina). In the skin, CLs are intercalated between epidermal keratinocytes suprabasally. On the ultrastructural level, they are characterized by the presence of a specific organelle of membrane origin, the Birbeck granule. In terms of immunohistochemistry, CLs express in particular the CD1a molecule and the molecules of the Major Histocompatibility Complex class II.
- CLs play a key role in immunity as antigen presenting cells. Indeed, experiments conducted in mice demonstrate that CLs capture the antigens present in the epidermis and migrate to the lymphoid tissues draining the skin, where they present the antigen to the T cells. The initiation of the immune response cutaneous depends on the ability of CL to leave the epidermis to migrate to the proximal ganglia. Different factors can influence this migration: the expression of adhesion molecules, extracellular matrix proteins, haptens, cytokines, etc. Nevertheless, the mechanisms involved in LC migration are not fully understood. In particular, before reaching the lymph nodes, CLs must not only cross the dermal-epidermal junction (JDE) but also make their way through the dermal extracellular matrix (ECM). JDE is mainly composed of laminin 5, type IV and VII collagen, nidogen and perlecan. The ECM that surrounds the fibroblasts of the dermis contains mainly type I and III collagens.
- IL-1 ⁇ interleukin-1-beta
- TNF- ⁇ Tumor Necrosis-alpha
- the present invention thus relates to the use of a composition comprising at least one active compound for inhibiting the migration of Langerhans cells chosen from the group of alkanolamides defined in the claims for obtaining a medicinal product intended for the treatment or for the prevention of the reactions or pathologies defined in the claims.
- the composition is a cosmetic or pharmaceutical composition, especially a dermatological composition, comprising at least one cosmetically or pharmaceutically acceptable excipient.
- the alkanolamides according to the invention correspond to the following general formulas: in which the radical R 1 represents a saturated linear alkyl group comprising from 2 to 40 carbon atoms (C 2 -C 40 ), advantageously 6 to 22 carbon atoms (C 6 -C 22 ), even more advantageously from 8 to 18 carbon atoms (C 8 -C 18 ), and even more advantageously from 10 to 16 carbon atoms (C 10 -C 16 ).
- R 1 is a linear saturated alkyl group in C 11.
- R 'and R independently represent a hydrogen atom, a methyl group or a linear C 2 -C 20 linear alkyl group.
- R 2 represents a hydrogen atom, a methyl group or a linear C 2 -C 20 linear alkyl group.
- the radical R 1 represents a saturated linear C 2 -C 40 , advantageously C 6 -C 22 , even more advantageously C 8 -C 18 and even more advantageously C 10 -C 8 alkyl group.
- 16 and R 'and R represent, independently, a hydrogen atom, a methyl group or a linear saturated alkyl group
- C 2 -C 20 and R 2 represents a hydrogen atom, a methyl group or a group linear saturated C 2 -C 20 alkyl.
- the said alkanolamide is the alkanolamide called AK100 of formula:
- the composition may further comprise at least one Langerhans cell migration inhibitor selected from the group consisting of matrix metalloprotease inhibitors (MMPs).
- MMPs matrix metalloprotease inhibitors
- MMPs matrix metalloprotease inhibitor compounds
- MMPs matrix metalloprotease inhibitor compounds
- fibroblasts keratinocytes, macrophages, endothelial cells, eosinophils, Langerhans cells, etc.
- MMPs thus consists of four subclasses: (1) collagenases, (2) gelatinases, (3) stromelysins and (4) membrane-type MMPs (MT-MMPs).
- the activity of MMPs can be modulated by naturally occurring proteinase inhibitors such as tissue inhibitors metalloproteinases (TIMPs, including TIMP-1 and TIMP-2).
- TIMPs tissue inhibitors metalloproteinases
- the active compound for inhibiting migration of Langerhans cells is an inhibitor compound of at least one MMP selected from the group consisting of MMP-1, MMP-2, MMP-3 MMP-9, MMP-13 and MMP-18.
- MMP inhibitor compound as an active compound for inhibiting the migration of Langerhans cells according to the present invention, is meant in particular the metalloproteinase tissue inhibitors (TIMPs), the alpha-2-macroglobulin, the inhibitors of plasminogen activator, zinc chelators, bryostatin-1, antibiotics (doxycyclines, minocyclines, etc.), synthetic or natural peptides having a structure similar to MMP substrates (batimastat, marimastat, etc.), retinoids (especially non-aromatic retinoids such as retinaldehyde, tretinoin, and 9-cis retinoic acid, vitamin A, monoaromatic retinoids such as etretinate, all-trans acitretin and motrerinide, and polyaromatic retinoids such as adapalene, tazarotene, tamibarotene and arotinoid methyl sulfone), antioxidants (s
- the MMP inhibitor compound according to the present invention is selected from the group consisting of peptide extracts of lupine or "lupine peptides", such as those described in the patent application. FR-99 04 875 filed on April 19, 1999 on behalf of Laboratoires Pharmascience. It may be mentioned in particular the peptide extract described in the application FR 99 04875 under the name extract B (LU105).
- said MMP inhibitor is selected from the group consisting of retinoids.
- the composition may also comprise at least one compound chosen from the group consisting of PKC inhibitors, anti-inflammatory agents, soothing agents, immunosuppressants, chelators of oxazolidinones, carbamic acid derivatives, especially (1-hydroxymethyl-tridecyl) -carbamic acid and (1-hydroxymethyl-undecyl) -carbamic acid, and oxazolines.
- This or these compound (s) selected from the group consisting of PKC inhibitors, anti-inflammatory agents, soothing agents, immunosuppressants, ion chelators, oxazolidinones, carbamic acid derivatives, especially (1-Hydroxymethyl) tridecyl) -carbamic acid and (1-Hydroxymethyl-undecyl) -carbamic acid, and the oxazolines allow (tent) to play on and / or limit the irritative reaction or sensitization even for some of them also to inhibit migration of dendritic cells, more particularly Langerhans cells, dermal dendrocytes, monocytes, lymphocytes, keratinocytes, mast cells and endothelial cells.
- dendritic cells more particularly Langerhans cells, dermal dendrocytes, monocytes, lymphocytes, keratinocytes, mast cells and endothelial cells.
- PLC Protein Kinase C
- PKC When activated, PKC phosphorylates specific serine or threonine residues on protein substrates, which vary by cell type. In many cells, activation of PKC increases the transcription of specific genes.
- Protein kinases C are proteins encoded by a family of genes (11 different isoforms). It is known in particular that these proteins are involved in the transduction of extracellular signals mediated by growth factors, cytokines, as well as by a number of other biological molecules.
- the protein kinase ⁇ 2 (PKC- ⁇ 2) appears specifically expressed by the CL of the epidermis.
- PKC inhibitory compound Any compound known to those skilled in the art as inhibiting the PKC phosphorylation activity can thus be used as a PKC inhibitory compound according to the present invention.
- the polypeptides described in the application WO 99/43805 (Incyte Genomics Inc.).
- the PKC inhibiting compound is selected from the group consisting of nonspecific PKC inhibitors, specific inhibitors of the PKC- ⁇ 2 isoform, and combinations thereof.
- the PKC inhibiting compound is selected from the group consisting of phenolic and polyphenolic compounds, procyanidines (catechins, epicatechins, etc.), alpha-amyrin, lupeol, lupeol linoleate, sterols, stanols, triterpenic alcohols and their hydrogenated counterparts, antibiotics such as staurosporine, Ro-318425 (or 2- (8) - (aminomethyl) -6,7,8,9-tetrahydropyridol (1,2-a) indol-3-yl) 3- (1-methyl-indol-3-ylmaleimide, HCl) as marketed by Calbiochem, the compounds which compete with the physiological activators of PKCs such as diacylglycerol and phorbol ester , cutaneous lipids of the (lyso) sphingolipid, lysophospholipid type such as ceramides and pseudoceramides, sphingos,
- phenolic and polyphenolic compounds is meant, according to the invention, simple phenols, benzoquinones, phenolic acids, acetophenones, phenylacetic acids, hydroxycinnamic acids, coumarins and isocoumarines, chromones, naftoquinones, xanthones, anthraquinones, flavonoids, lignans and neolignans, lignins, chalcones, dihydrochalcones, aurones, flavones, flavonols, dihydroflavonols, flavanones, flavanols, flavandiols or leucoanthocyanidines, anthocyanidins, isoflavonoids, biflavonoids, proanthocyanidines and condensed tannins.
- sterols is meant more particularly according to the invention the sterol, ie the perhydro-1,2-cyclopentanophenanthrene compound having a hydroxyl group at the 3-position, and the sterol analogues of general formula (I) below.
- the sterols that can be used according to the invention have the following general formula: in which the dotted unsaturation at position 5 corresponds to the unsaturation in the case of sterols, R represents a hydrocarbon chain, linear or branched, unsaturated or unsaturated, having from 1 to 25 carbon atoms.
- R is chosen from the group consisting of alkyl C 1 -C 12 alkoxy C 1 -C 8 alkenyl, C 2 -C 8 alkynyl groups, C2 - C8 cycloalkyl C 3 -C 8 alkenyl, C 2 -C 8 halogenated alkynyl groups, C 2 -C 8 halogenated.
- halogenated refers to one or more halogen substituents, that is, one or more chlorine, fluorine, bromine or iodine atom (s).
- ⁇ -sitosterol may be used in the form of the product called "Ultra” (mainly comprising ⁇ -sitosterol) as marketed by Kaukas.
- ⁇ -sitosterol may be used in the form of the product called "Ultra” (mainly comprising ⁇ -sitosterol) as marketed by Kaukas.
- Generol mainly comprising ⁇ -sitosterol (about 50% by weight), stigmasterol, brassicasterol and campesterol as marketed. by the company Cognis or the product "Primal” from the company Kaukas.
- triterpene alcohols which can advantageously be used according to the invention, there may be mentioned in particular ⁇ -amyrin, erythrodiol, taraxasterol, cycloartol, 24-methylenecycloartanol, lupeol, lanosterol and mixtures thereof .
- the term "hydrogenated homologues" of a triterpene alcohol is intended to mean the corresponding triterpene alcohol (s) alcohol (s) whose unsaturated bond (s), if any, may be present (s). were hydrogenated (ie transformed into saturated bond) according to methods well known to those skilled in the art.
- sphingolipids there may be mentioned those of the most elementary such as sphingosine (D erythro dihydroxy 1,3 amino 2 octadecene 4t) and its isomers, phytosphingosine (D ribo trihydroxy 1,3,4 amino 2 octadecane) and its isomers. But also, lysosphingolipids (among them, lysosulfatide and psychosine), sulfogalactosylsphingosine, sphinganine (2-amino 1,3 octadecane diol) and sphingomyelines.
- Phospholipids that may be mentioned include those from the families of phosphatidylaminoalcohols and phosphatidylpolyols.
- the group of phosphatidylamino-alcohols includes phosphatidylethanolamines (or phosphatidylcolamines), phosphatidylcholines, phosphatidylserines, N-acylphosphatidylethanolamines.
- That of phosphatidylpolyols comprises, in turn, phosphatidylcholinositols, diphospho-inositides, lysodiphospho-inositides, phosphatidylglycerols and cardiolipids.
- the ceramides can be chemically synthesized (in particular pseudo-ceramides), be of animal origin (relatively high concentrations of sphingolipids are present in the mammalian brain and spine), plant origin (mainly cerebrosides and other glycosylated sphingolipids) or be yeast derivatives (stereochemical configuration identical to that of ceramides naturally present in human skin).
- the ceramides of the intercorneocytic cement of the epidermis can be separated by conventional methods (thin layer chromatography) into six fractions, corresponding to compounds differing by the nature of the fatty acids and the nature of the base involved (sphingosines, unsaturated, or phytosphingosines, saturated). Table 1 next illustrates the respective structures present in these fractions, according to the Werts and Downing classification. Fraction 6 can itself be subdivided by finer methods into two entities: ceramides 6a and 6b.
- ceramides 1, less polar have a very particular structure, found in ceramide 6a: a long-chain omega-hydroxy acid amide base, and attached at its end omega by an ester bond to another fatty acid (O-acylceramides).
- the sphingosine-bound fatty acids are essentially C24, C26, C30, C32 or C34, which may be saturated, monoethylenic (mainly for C30, C32 and C34) or diethylenic (C32 and especially C34 ).
- the fatty acid attached to the omega end of the previous one it is predominantly for ceramides 1, linoleic acid, the key role in the hybrid barrier function of the epidermis is well known.
- Fraction 2 of more conventional structure (sphingosines or dihydrosphingosines linked by an amide linkage to a fatty acid, mainly C20 to C28), is the most abundant.
- Fraction 3 is quite similar, the difference being in the nature of the base, which in this case is essentially represented by the saturated phytosphingosines.
- Fractions 4 and 5 are essentially characterized by the presence of sphingosine-bound alpha-hydroxy acids.
- Fraction 6b is close to fractions 4 and 5, having an alpha hydroxy acid, but bound to a phytosphingosine, saturated.
- Fraction 6a like ceramide 1, has the characteristic pattern found only at the ceramide level of the epidermis, that is to say the ester bond between the omega hydroxyl of an acid. fat bound to a sphingosine, and the carboxylic moiety of a terminal fatty acid, which this time is not linoleic acid, but an alpha-hydroxy acid.
- phytoceramides phytosphingosine-based ceramides
- synthetic cholesterol-ceramides synthetic cholesterol-ceramides
- galacto or gluco cerebrosides synthetic cholesterol-ceramides
- sphingosine is naturally present in the skin, and inter alia plays an important role in the barrier function of the stratum corneum, as a precursor of sphingolipids ( ceramides and sphingoglycolipids). It can be derived from a biological source such as extracts of bovine brains or by synthesis, from serine, as described for example in the article of Newman, J.Am. CHEM., 95 (12): 4098 (1973) ). It is more particularly possible to mention the isomeric forms of sphingosine: D-erythro, L-threo, L-erythro and D-threo. The D-erythro form is most frequently present in nature.
- the PKC inhibiting compounds that can be used include the isomers, derivatives (salts, complexes, etc.), analogs, homologues, precursors and metabolites of the PKC inhibiting compounds described above.
- anti-inflammatory agents that can be used in the context of the present invention in combination with the alkanolamides are advantageously steroidal anti-inflammatory agents (AIS), such as steroids, or non-steroids (NSAIDs).
- AIS steroidal anti-inflammatory agents
- NSAIDs non-steroids
- the soothing agents that can be used in the context of the present invention in combination with the alkanolamides are advantageously liquorice derivatives and derivatives of alpha-bisabolol.
- immunosuppressants that can be used in the context of the present invention in combination with the alkanolamides are advantageously tacrolimus, pimecrolimus, and cyclosporine.
- the ion chelators that can be used in the context of the present invention in combination with the alkanolamides are advantageously chemical chelators advantageously chosen from the group consisting of ethylenediaminetetraacetic acid (EDTA) and its sodium and potassium salts. disodium calcium, diammonium, triethanololamine (TEA-EDTA), hydroxyethylethylene diamine tetracetic acid (HEDTA) and its trisodium salt, diethylenetriamine pentaacetic acid (DTPA), and mixtures thereof.
- the ion chelators may also be biological chelators advantageously selected from the group consisting of metallothionein, transferin, lactoferin, calmodulin, chitosan methylene phosphonate, and mixtures thereof.
- the chelated ions are advantageously the ions Na + , K + , Ca 2+ , Cl - , Ni 2+ , Co + , Co 2+ , Zr 2+ , Zr 4+ , but also the chromium ions at the oxidation level II and III such as Cr 2+ , Cr 3+ , and Cr 2 O 7 2- .
- oxazolines which can be used in the context of the present invention in combination with the alkanolamides are advantageously oxazolines corresponding to the following general formulas: in which R 1 represents a linear or branched, saturated or unsaturated C 1 -C 40 alkyl group optionally comprising one or more ethylenic unsaturation (s) and also one or more substituents chosen from the group formed by the hydroxyl (OH) and C 1 -C 6 alkoxy radicals (OC 1 -C 6 ); R 2 , R 3 , R 4 and R 5 independently represent a hydrogen atom, a hydroxyl radical or a linear or branched, saturated or unsaturated C 1 -C 30 alkyl group optionally comprising one or several ethylenic unsaturations as well as one or more substituent (s) chosen from the group consisting of hydroxyl (OH), C 1 -C 6 alkoxy (OC 1 -C 6 ) and C 1 -C 6 alkoxy radicals carbon
- said oxazoline is a type 1 oxazoline selected from the group consisting of 2-undecyl-4-hydroxymethyl-4-methyl-1,3-oxazoline, 2-undecyl-4,4-dimethyl-1,3-oxazoline, (E) -4,4-dimethyl-2-heptadec-8-enyl-1,3-oxazoline, 4-hydroxymethyl-4-methyl -2-heptadecyl-1,3-oxazoline, (E) -4-hydroxymethyl-4-methyl-2-heptadec-8-enyl-1,3-oxazoline, 2-undecyl-4-ethyl-4-hydroxymethyl -1,3-oxazoline.
- said oxazoline is 2-undecyl-4,4-dimethyl-1,3-oxazoline, called OX-100, of formula:
- R 1 represents a hydrogen atom.
- R 2 represents a saturated linear C 8 -C 22 , advantageously C 9 -C 18 , even more advantageously C 9 -C 13 alkyl group, even more advantageously C 11 -C 12. -C 13 , and / or R ' 2 represents a hydrogen atom.
- R 3 and R ' 3 represent a hydrogen atom.
- R 4 and R 5 represent a hydrogen atom.
- R 1 represents a hydrogen atom
- R 2 represents a saturated linear C 8 -C 22 , advantageously C 9 -C 18 , even more advantageously C 9 -C 13 alkyl group. , even more advantageously C 11 -C 13
- R ' 2 , R 3 , R' 3 , R 4 and R 5 represent a hydrogen atom.
- the carbamic acid derivative is chosen from the group consisting of (1-hydroxymethyl-tridecyl) -carbamic acid and (1-hydroxymethyl-undecyl) -carbamic acid.
- R 1 represents a hydrogen atom.
- R 2 represents a linear saturated alkyl group in C 8 -C 22, preferably C 9 -C 18, even more advantageously C 9 -C 12, even more advantageously in C 10 -C 11 , and / or R ' 2 represents a hydrogen atom.
- R 3 and R ' 3 represent a hydrogen atom.
- R 1 represents a hydrogen atom
- R 2 represents a saturated linear C 8 -C 22 , advantageously C 9 -C 18 , even more advantageously C 9 -C 12 alkyl group. even more advantageously C 10 -C 11
- R ' 2 , R 3 and R' 3 represent a hydrogen atom.
- the oxazolidinone is chosen from the group consisting of 4-dodecyl-oxazolidin-2-one, 3,4-didodecyl-oxazolidin-2-one and 4,5-didodecyl-oxazolidin-2-one.
- 4-dodecyl-oxazolidin-2-one can be represented by the following formula:
- 3,4-Didodecyl-oxazolidin-2-one may be represented by the following formula:
- 4,5-Didodecyl-oxazolidin-2-one can be represented by the following formula:
- Oxazolines, oxazolidinones and carbamic acids are compounds inhibiting migration of Langerhans cells.
- the composition is characterized in that the concentration of alkanolamide is advantageously between about 0.001 and about 10% by weight, and more particularly between about 0.01 and 3% by weight, relative to the total weight of the composition.
- the composition is advantageously a cosmetic or pharmaceutical composition, especially a dermatological composition.
- the composition may be formulated as various preparations suitable for topical administration, oral or rectal administration, parenteral administration.
- the different preparations are suitable for topical administration and include creams, ointments, lotions, oils, patches, sprays or any other products for external application.
- the modes of administration, the dosages and the optimal dosage forms of the compounds and compositions according to the invention can be determined according to the criteria generally taken into account in the establishment of a cosmetic or pharmaceutical treatment, preferably a dermatological treatment, adapted to a particular patient such as the age or body weight of the patient, the severity of his general condition, the tolerance to treatment, the side effects noted, the type of skin.
- composition and / or the active compounds according to the invention may further comprise at least one cosmetically acceptable or pharmaceutically acceptable excipient, in particular dermatologically acceptable excipient.
- an excipient suitable for external topical administration is used.
- the composition according to the present invention may further comprise at least one adjuvant cosmetically or pharmaceutically known to those skilled in the art, chosen from thickeners, preservatives, perfumes, dyes, chemical or mineral filters, moisturizing agents, thermal waters, etc.
- the medicament is intended for the treatment or prevention of allergic and / or inflammatory and / or irritating reactions and pathologies of the skin and / or mucous membranes, in particular of the mouth, lungs, bladder, rectum, vagina.
- the drug is suitable for the treatment and / or prevention of reactions or pathologies of the skin and / or mucous membranes resulting from the migration of cells, such as Langerhans cells, induced by a danger signal.
- danger signal means any signal that generates in particular the production of inflammatory cytokines or any true immunological signal of the type of penetration of an allergen.
- the medicament is intended for the treatment and / or prevention of reactions or pathologies induced by chemical or metallic haptens.
- the medicament is intended for the treatment or prevention of sensitive and / or reactive skins and / or mucous membranes and / or uncomfortable and / or intolerant and / or having a barrier disorder dermal and / or immunological imbalance related to intrinsic aging, extrinsic (sun, pollution) or hormonal.
- composition according to the invention makes it possible to reduce the immune response induced by the migration of CL having fixed IgE on the surface. Therefore, the present invention also relates to the use of a composition according to the invention and intended to inhibit the migration of Langerhans cells or of at least one active compound chosen from the group of alkanolamides as defined previously for the treatment or prevention of atopic eczema.
- the composition according to the invention, as well as the active compounds according to the invention are also intended for the treatment or prevention of contact eczema, insofar as they make it possible to reduce an immune response, in particular induced by capture of a antigen, treatment and presentation of this antigen to T cells by CL.
- compositions are also used for the treatment and / or the prevention of inflammatory pathologies, in particular inflammatory dermatoses such as psoriasis, irritative dermatitis, autoimmune diseases, prevention of photoimmunity. -suppression or transplant rejection.
- inflammatory pathologies in particular inflammatory dermatoses such as psoriasis, irritative dermatitis, autoimmune diseases, prevention of photoimmunity. -suppression or transplant rejection.
- photoimmuno-suppression is intended to denote a decrease in the immune response induced by the solar ultra-violet, and more particularly by the ultraviolet B.
- compositions are also used to reduce the allergenic and / or irritant nature of a composition, which may be a pharmaceutical preparation or a cosmetic preparation, or a perfume.
- allergenic character is meant the power of certain compounds contained in said compositions to behave like allergens, that is to say compounds capable of inducing an immediate and / or inflammatory hypersensitivity reaction.
- the active compound chosen from the group of alkanolamides as defined above it may be used in combination with at least one compound, a Langerhans cell migration inhibitor, selected from the group consisting of matrix metalloprotease inhibitors (MMPs), PKC inhibitors, anti-inflammatory agents, soothing agents, immunosuppressants, ion chelators, oxazolidinones, carbamic acid derivatives and oxazolines as defined previously.
- MMPs matrix metalloprotease inhibitors
- the composition and the active compounds are advantageously intended for use in cosmetology.
- the present invention also relates to a composition as defined in the claims for its use of a method for treating skins and / or mucous membranes selected from the skin, and / or the mucous membranes that are sensitive, irritated, intolerant, with an allergic tendency, aged, subject to a danger signal, presenting a cutaneous barrier disorder, presenting cutaneous redness, or presenting a non-pathological immunological disorder or imbalance related to intrinsic, extrinsic or hormonal aging, characterized in that it consists in applying to the skin and / or the mucous membranes a composition or at least one active compound chosen from the group of alkanolamides as defined above.
- the active compound chosen from the group of alkanolamides as defined above may also be applied in combination with at least one other compound selected from the group consisting of matrix metalloprotease inhibitors (MMPs), PKC inhibitors, anti-inflammatory agents , soothing agents, immunosuppressants, ion chelators, oxazolidinones, carbamic acid derivatives and oxazolines as defined above.
- MMPs matrix metalloprotease inhibitors
- PKC inhibitors PKC inhibitors
- anti-inflammatory agents e.g., anti-inflammatory agents, soothing agents, immunosuppressants, ion chelators, oxazolidinones, carbamic acid derivatives and oxazolines as defined above.
- the non-pathological immunological disorder or imbalance is a temporary imbalance or not of the immune function of the skin without gravity.
- Example 1 Example of Composition According to the Present Invention
- Epidermal cell suspensions were obtained by enzymatic treatment (0.05% trypsin, for 18 h at + 4 ° C) of normal human skin fragments from plastic surgery.
- the suspensions obtained contain on average 2 to 4% of CL.
- Obtaining suspensions containing on average 70% CL, is based on the principle of density gradient centrifugation (Lymphoprep TM) and removal of keratinocytes.
- the baseline chosen for the entire study was RPMI 1640 (Gibco BRL, France).
- DNSB (Sigma Aldrich), a soluble form of DNCB (dinitro-chloro-benzene), solubilized in RPMI-BSA and used at a concentration of 50 ⁇ M, was used as sensitizing agent.
- a two-compartment culture chamber system (Falcon, Becton Dickinson, France) was used.
- the upper compartment is separated from the lower compartment by a membrane of porosity 8 ⁇ m, on which are deposited 50 ⁇ g / cm 2 of Matrigel.
- the membrane is then covered with proteins forming a film equivalent to a basement membrane (laminin, collagen IV, nidogen, entactin, heparan sulfate proteoglycans).
- the cells taken up in RPMI-BSA medium alone or in the presence of the different products are deposited in the upper compartment.
- In the lower compartment is added human fibroblast culture supernatant normal.
- the results represent the ratio between the number of cells that migrated in the presence of DNSB +/- AK100 and the number of cells that migrated under normal conditions (non-sensitized and untreated control cells).
- Freshly isolated CLs from the epidermis do not have a high migratory capacity.
- the migratory capacity of the CL controls (untreated and non-sensitized) is arbitrarily set at 1.
- AK100 at the concentration of 1 ⁇ M significantly inhibits DNSB-induced CL migration.
- the cells thus treated have a migration index comparable to that of the non-sensitized control cells.
- the inventors have shown using freshly isolated CLs placed in a two-compartment culture chamber system (allowing cell migration) that, quite surprisingly, AK100 significantly inhibits CL migration. Under the experimental conditions used by the inventors, the cells treated with AK100 have a migration index comparable to that of the non-sensitized control cells.
- Example 3 Study of the activity of the AK100 on the inhibition of the migration of dendritic cells generated in vitro from CD34 + precursors from cord blood
- Mononuclear cells were obtained from umbilical cord blood from healthy donors by Ficoll centrifugation.
- the CD34 + cells were then purified by immunoselection using specific antibodies and magnetic beads (Miltenyi Biotech, Germany).
- the CD34 + cells were cultured in the presence of GM-CSF (100 ng / ml), TNF- ⁇ (2.5 ng / ml) in RPMI supplemented with 10% fetal calf serum, for 5 days.
- TGF- ⁇ 1 a factor which promotes the differentiation of cells towards the Langerhans cell pathway, was carried out on the 5th day of culture.
- the cells were treated on day 7 with the BB hapten (Brandowski base, 1.17 ⁇ g / ml) for 24 h and then subjected to the migration test.
- BB hapten Brandowski base, 1.17 ⁇ g / ml
- the results represent the percentage of cells that migrated in the presence of the different products tested.
- the percentage is calculated by relating the number of cells recovered in the lower compartment of the migration chamber to the number of cells subjected to migration.
- AK100 inhibits the migration of dendritic cells by 51% and 25%, respectively.
- AK100 at a concentration of 1 ⁇ M significantly inhibits the migration of dendritic cells generated in vitro and activated by the BB hapten.
- FITC Fluorescein isothiocyanate, Sigma, St. Louis, MO
- Alkanolamide AK100 and LU105 (LU 105 is an MMP inhibitor, corresponding to a peptide extract of white lupine marketed by the Company. Expanscience under the brand name Actimp 193®) were provided by "Laboratoires Expanscience", and formulated alone or in combination in an inert vehicle compatible with topical application, as described in Example 1 above [Alkanolamide AK100 (0.1%) ⁇ LU105 (2%)]. The different formulations were applied to the mouse ears twice daily for 4 consecutive days. Three hours after the last application, 1.5% FITC is applied to both ears (one treated and the other untreated (Control)).
- mice The effect of the two molecules was evaluated in vivo in mice.
- the skin of both ears is brushed with 1.5% FITC (2X5 .mu.l).
- FITC FITC
- the tissues were cut and the cells were separated by filtration (100 ⁇ M filter, Falcon, Becton Dickinson) and washed.
- the cells are then centrifuged for 10 min at 600 xg (mxs -2 ) on a metrizamide gradient (14.5% in RPMI 1640, 7.5% FCS).
- the cells of the interface are recovered, rinsed and then labeled with an anti-CDS86 PE-conjugate, biot-MHC CLII mAbs plus streptavidin-Cya (PharMingen) and analyzed by flow cytometry. Only the FITC +, PE + and Cya + cells are counted because they represent the population of cells that migrated from the skin to the GLs following the application of the hapten.
- Topical application of the vehicle alone does not result in any change in the number of FITC + CDs at the GL level.
- the vehicle has no effect on the migratory capacities of CDs.
- FITC Fluorescein isothiocyanate, Sigma, St. Louis, MO
- mice The effect of the two molecules was evaluated in vivo in mice.
- the skin of both ears is brushed with 1.5% FITC (2X5 .mu.l).
- FITC FITC
- the tissues were cut and the cells were separated by filtration (100 ⁇ M filter, Falcon, Becton Dickinson) and washed.
- the cells are then centrifuged for 10 min at 600 xg (mxs -2 ) on a metrizamide gradient (14.5% in RPMI 1640, 7.5% FCS).
- the cells of the interface are recovered, rinsed and then labeled with an anti-CDS86 PE-conjugate, biot-MHC CLII mAbs plus streptavidin-Cya (PharMingen) and analyzed by flow cytometry. Only cells that have migrated from the skin to the GL following the application of the hapten.
- Topical application of the vehicle alone does not result in any change in the number of FITC + CDs at the GL level.
- the vehicle has no effect on the migratory capacities of CDs.
- a cosmetic day cream comprising 0.1% by weight of AK100 and 2% by weight of peptide extract of white lupine, LU105, relative to the total weight of the cream, was tested in human volunteers, with collaboration of dermatologist doctors.
- the main goals are to evaluate the clinical efficacy and cosmetic acceptability of said day cream in the context of normal use of the product.
- the product of the test made available to the practitioner with the necessary public information, has been proposed by the Dermatologist to his patient by specifying sufficient modalities of daily applications, ie at least 2 applications per day.
- the product was applied on the face morning and evening on a clean and dry skin.
- results are evaluated on a scale from 0 to 9.
- a score of 0 corresponds to a change in the skin, before and after treatment, zero
- a rating ranging from 1 to 3 corresponds to a change in the skin, before and after treatment, slight
- a rating ranging from 4 to 6 corresponds to a change in the skin, before and after treatment, moderate
- a rating ranging from 7 to 9 corresponds to a change in the skin, before and after treatment, important.
- Said cream formulated without perfume or dye, thus ensures effective hydration of the upper layers of the epidermis and provides an appropriate response to hypersensitive skin, irritated or allergic predisposition.
- AK100 in combination with LU105 almost completely inhibits the migration of CDs to GLs.
- AK100 and LU105 act synergistically to inhibit CD migration in sensitized mice.
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Claims (8)
- Verwendung einer Zusammensetzung, umfassend einen für eine Verabreichung auf externem topischem Weg geeigneten Arzneiträger und mindestens eine aktive Verbindung, um die Migration des Langerhans-Zellen zu hemmen, ausgewählt aus der Gruppe der Alcanolamide, die den folgenden allgemeinen Formeln entsprechen:wobei R1 eine gesättigte lineare C2-C40-Alkylgruppe darstellt;R' und R" unabhängig ein Wasserstoffatom, eine Methylgruppe oder eine gesättigte lineare C2-C20-Alkylgruppe darstellen,R2 ein Wasserstoffatom, eine Methylgruppe oder eine gesättigte lineare C2-C20-Alkylgruppe darstellt,um ein Arzneimittel zu erhalten, das für die Behandlung oder Prävention von Reaktionen oder Pathologien der Haut und/oder der Schleimhäute nach einer Migration der Langerhans-Zellen bestimmt ist, ausgewählt aus der Gruppe, die gebildet ist von:- den allergischen Reaktionen oder Pathologien,- den entzündlichen Reaktionen oder Pathologien,- dem atopischen und/oder Kontaktekzem,- den entzündlichen Dermatosen wie die Psoriasis,- den irritativen Dermatitiden,- den Autoimmunkrankheiten,- der Photo-Immunsuppression und- der Transplantatabstoßung.
- Verwendung nach Anspruch 1, dadurch gekennzeichnet, dass R1 eine gesättigte lineare C6-C22-, in vorteilhafter Weise C6-C18- und noch vorteilhafter C10-C16-Alkylgruppe darstellt.
- Verwendung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass sie ferner mindestens einen Metallproteasenhemmer umfasst, der aus der Gruppe ausgewählt ist, die von den Peptidextrakten der Lupine, vorzugsweise vom Extrakt B (LU105), oder den Retinoiden gebildet ist.
- Verwendung nach einem der vorangehenden Ansprüche, dadurch gekennzeichnet, dass die Alkanolamidkonzentration in der Zusammensetzung zwischen zirka 0,001 und zirka 10 Gew.-% inklusive in Bezug zum Gesamtgewicht der Zusammensetzung beträgt.
- Verwendung nach einem der vorangehenden Ansprüche, dadurch gekennzeichnet, dass das Arzneimittel für die Behandlung oder die Prävention der Reaktionen oder Pathologien bestimmt ist, die von chemischen oder metallischen Haptenen induziert werden.
- Verwendung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass das Arzneimittel bestimmt ist, den allergieauslösenden und/oder irritierenden Charakter einer Zusammensetzung oder eines Duftstoffs zu verringern.
- Zusammensetzung, wie nach einem der Ansprüche 1 bis 5 definiert, für ihre Verwendung in einer Behandlungsmethode der sensiblen, irritierten, intoleranten, eher allergischen Haut und/oder der Schleimhäute, die einem Gefahrensignal ausgesetzt sind, eine Störung der Hautbarriere aufweisen, Hautrötungen aufweisen, dadurch gekennzeichnet, dass sie auf die Haut und/oder die Schleimhäute aufgetragen wird.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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FR0116916 | 2001-12-27 | ||
FR0116916A FR2834213B1 (fr) | 2001-12-27 | 2001-12-27 | Composition cosmetique ou pharmaceutique comprenant au moins une alcanolamide pour inhiber la migration des cellules de langerhans, et ses utilisations |
PCT/FR2002/004582 WO2003055462A2 (fr) | 2001-12-27 | 2002-12-27 | Composition comprenant au moins un alcanolamide pour inhiber la migration des cellules de langerhans, et ses utilisations. |
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EP1458347B1 true EP1458347B1 (de) | 2016-09-28 |
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US (2) | US20050075397A1 (de) |
EP (1) | EP1458347B1 (de) |
JP (1) | JP4898089B2 (de) |
KR (1) | KR20040094402A (de) |
CN (1) | CN1617703B (de) |
AU (1) | AU2002364348A1 (de) |
CA (1) | CA2472121A1 (de) |
FR (1) | FR2834213B1 (de) |
MX (1) | MXPA04006420A (de) |
WO (1) | WO2003055462A2 (de) |
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FR2847473B1 (fr) | 2002-11-25 | 2007-06-29 | Expanscience Lab | Composition comprenant au moins une oxazolidinone, son utilisation cosmetique et comme medicament |
JP2006206538A (ja) * | 2005-01-31 | 2006-08-10 | Institute Of Physical & Chemical Research | 抗原提示細胞の機能制御剤 |
JP4965807B2 (ja) * | 2005-03-30 | 2012-07-04 | 日光ケミカルズ株式会社 | 外用剤用組成物およびそれを含有する皮膚外用剤 |
KR20080055852A (ko) * | 2005-08-31 | 2008-06-19 | 세렌티스 리미티드 | 스타필로코커스 아우레우스에 의한 콜로니화를 특징으로하는 염증성 피부 병태의 치료를 위한 아우레오리신억제제의 용도 |
JP2007269671A (ja) * | 2006-03-30 | 2007-10-18 | Redox Bioscience Inc | アレルギー性皮膚炎の予防ないし治療剤 |
FR2908650B1 (fr) * | 2006-11-16 | 2012-05-25 | Lvmh Rech | Utilisation d'une alkyloxazolidinone comme agent cosmetique hydratant et procede d'hydratation de la peau. |
IL187247A0 (en) | 2007-11-08 | 2008-12-29 | Hadasit Med Res Service | Novel synthetic analogs of sphingolipids |
JP6480839B2 (ja) * | 2015-09-25 | 2019-03-13 | 富士フイルム株式会社 | セラミド分散組成物 |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US101580A (en) * | 1870-04-05 | Improved device for ringing street-car bells | ||
US138177A (en) * | 1873-04-22 | Improvement in box-openers | ||
US215414A (en) * | 1879-05-13 | Improvement in paper-damping machines | ||
US59447A (en) * | 1866-11-06 | Improvement in churn and washing-machine combined | ||
US4876249A (en) | 1987-01-12 | 1989-10-24 | Rajadhyaksha Vithal J | Compositions and method comprising heterocyclic compounds containing two heteroatoms |
US5235076A (en) * | 1991-05-28 | 1993-08-10 | University Of Hawaii | Azulenic retinoid compounds, compositions and methods |
JPH08512060A (ja) * | 1994-04-27 | 1996-12-17 | ギスト ブロカデス ベスローテン フェンノートシャップ | 短鎖2−ヒドロキシカルボン酸をベースにしたセラミド誘導体 |
WO1996016635A1 (en) * | 1994-11-28 | 1996-06-06 | Gist-Brocades B.V. | Topical application of ceramides |
KR19980034991A (ko) * | 1996-11-11 | 1998-08-05 | 안용찬 | 비천연세라미드 관련화합물 및 이를 함유하는 피부외용제 |
WO1999029293A1 (en) * | 1997-12-05 | 1999-06-17 | Dsm N.V. | Compositions comprising a combination of a free sphingoid base and a ceramide and uses thereof |
US6610835B1 (en) * | 1998-02-12 | 2003-08-26 | Emory University | Sphingolipid derivatives and their methods of use |
US6218113B1 (en) * | 1998-02-24 | 2001-04-17 | Incyte Genomics, Inc. | Human protein kinase C inhibitor |
FR2780727B1 (fr) * | 1998-07-03 | 2000-09-08 | Atochem Elf Sa | Compositions cosmetiques, nouveaux analogues de ceramides a activite anti-elastase, procede de preparation et utilisations |
DE19841794A1 (de) * | 1998-09-12 | 2000-03-16 | Beiersdorf Ag | Kombinationen von Antiadhäsiva (Ceramide und Sphingosine und Derivate) und Mikrobiziden |
US6159485A (en) * | 1999-01-08 | 2000-12-12 | Yugenic Limited Partnership | N-acetyl aldosamines, n-acetylamino acids and related n-acetyl compounds and their topical use |
FR2792202B1 (fr) | 1999-04-19 | 2003-06-13 | Pharmascience Lab | Extrait peptidique de lupin et composition pharmaceutique ou cosmetique ou nutraceutique comprenant un tel extrait |
US6630163B1 (en) * | 1999-04-22 | 2003-10-07 | Howard Murad | Method of treating dermatological disorders with fruit extracts |
FR2823117A1 (fr) * | 2000-11-14 | 2002-10-11 | Pharmascience Lab | Composition pharmaceutique ou cosmetique ainsi que l'utilisation d'au moins un compose actif pour inhiber la migration des cellules de langerhans |
KR100404072B1 (ko) | 2001-03-12 | 2003-11-03 | 주식회사 두산 | 광범위 피부질환 치료용 조성물 |
FR2826011B1 (fr) * | 2001-06-14 | 2004-12-10 | Oreal | Nouveaux derives de la 7-oxo-dhea et utilisation cosmetique |
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2001
- 2001-12-27 FR FR0116916A patent/FR2834213B1/fr not_active Expired - Lifetime
-
2002
- 2002-12-27 CN CN028276833A patent/CN1617703B/zh not_active Expired - Fee Related
- 2002-12-27 JP JP2003556040A patent/JP4898089B2/ja not_active Expired - Lifetime
- 2002-12-27 AU AU2002364348A patent/AU2002364348A1/en not_active Abandoned
- 2002-12-27 KR KR10-2004-7010260A patent/KR20040094402A/ko not_active Application Discontinuation
- 2002-12-27 US US10/499,977 patent/US20050075397A1/en not_active Abandoned
- 2002-12-27 CA CA002472121A patent/CA2472121A1/fr not_active Abandoned
- 2002-12-27 EP EP02799126.4A patent/EP1458347B1/de not_active Expired - Lifetime
- 2002-12-27 WO PCT/FR2002/004582 patent/WO2003055462A2/fr active Application Filing
-
2004
- 2004-06-28 MX MXPA04006420A patent/MXPA04006420A/es unknown
-
2006
- 2006-04-27 US US11/411,870 patent/US8304453B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
US20060194881A1 (en) | 2006-08-31 |
AU2002364348A8 (en) | 2003-07-15 |
WO2003055462A2 (fr) | 2003-07-10 |
CN1617703B (zh) | 2010-12-01 |
MXPA04006420A (es) | 2004-10-04 |
AU2002364348A1 (en) | 2003-07-15 |
FR2834213A1 (fr) | 2003-07-04 |
CA2472121A1 (fr) | 2003-07-10 |
EP1458347A2 (de) | 2004-09-22 |
US20050075397A1 (en) | 2005-04-07 |
US8304453B2 (en) | 2012-11-06 |
WO2003055462A3 (fr) | 2004-01-22 |
CN1617703A (zh) | 2005-05-18 |
FR2834213B1 (fr) | 2004-06-04 |
KR20040094402A (ko) | 2004-11-09 |
JP4898089B2 (ja) | 2012-03-14 |
JP2005518390A (ja) | 2005-06-23 |
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